Retrospective Study of Oral Lichen Planus and Oral Lichenoid Lesions: Clinical Profile and Malignant Transformation

Statement of the Problem: Oral lichen planus (OLP) and other oral lichenoid lesions (OLL) are reported to have the potential of malignant transformation and dysplastic changes, turning into oral squamous cell carcinoma (SCC). While the world health organization (WHO) has classified OLP as a precancerous lesion of the oral cavity, there is still much debate among researchers about its risks and malignancy potential. Purpose: The present study aimed to determine malignant transformation in OLP and OLL and understand related risk factors. Materials and Method: This retrospective study was performed on 356 patients of the Oral Medicine Department of Dental School of Kerman Medical University from 1998 to 2020. All patients’ records were gathered. In addition, patients were followed up routinely. Second biopsy was taken as needed. The samples, previously taken from the patients, were re-evaluated according to WHO histopathologic criteria for diagnosing OLP, OLL, dysplasia, and SCC by an experienced pathologist and compared with first reports. Results: Dysplastic changes were observed in 6.2% of the patients. In more than half of the patients, dysplastic changes were present right from the start and 2.20% of the patients had experienced dysplastic changes averagely within 2.05 years of the onset of lesions. Multiple logistic regression showed that the risk of dysplasia increases with aging (p= 0.013), smoking (p= 0.0001), and thyroid disorders (p= 0.008). Conclusion: Given the rather high prevalence of oral lichen planus and lichenoid lesions, further research appears to be needed to determine the etiology of these lesions, malignant transformations, and the factors affecting this probability. Considering the findings, it is imperative to meticulously record the information of all patients with oral lichen planus and lichenoid lesions in the initial examinations as well as close follow-ups and employ diagnostic tools such as toluidine blue staining or even repeat biopsy when necessary.


Introduction
Oral lichen planus (OLP) is a common chronic inflammatory mucocutaneous disorder. This disorder usually affects the oral mucosa, but can also occur on the skin, genital mucosa, scalp, and nails [1]. The global prevalence of OLP has been estimated at 0.5-2.6%. Research has shown that the mean age of onset of OLP is 50-60 years and it is more common in women than in men by a ratio of 3 to 2 [1]. OLP lesions manifest as bilateral white keratotic lines with reticular and radial patterns (Wickham striae) in an atrophic or erosive bed [1].
There is another group of oral lesions with almost the same clinical and histopathological characteristics as OLP, which are called oral lichenoid lesions (OLL) or oral lichenoid reactions (OLRs). These include contact hypersensitivity to dental materials, drug-induced lichenoid lesions, lichenoid reactions in chronic graft-versushost disease, and lichenoid dysplasia [1]. Histopathological examinations alone are not enough to differentiate between OLLs and OLP reliably. For this differentiation, one has to also examine the clinical characteristics of the lesions and make a diagnosis based on the diagnostic criteria provided by the world health organization (WHO) in 2003. However, even with these criteria, it is sometimes impossible to differentiate these lesions [2].
One of the most important issues regarding OLP is the potential for malignancy and the possibility of dysplastic changes and conversion to oral squamous cell carcinoma (SCC). Although the WHO has classified OLP as a potentially malignant condition, there is still much debate among researchers about the malignancy potential and risk of OLP [3]. The mechanism that causes OLP to become malignant is not exactly known. It has been suggested that chronic inflammation in these lesions and inflammatory mediators can lead to genetic changes in the epithelium that accelerate malignant transformation [4].
Some researchers have suggested that only OLLs, and not OLP, are malignant and should be classified as lichenoid dysplasia [5]. However, there have been numerous reports of SCC in patients who have previously been diagnosed with OLP without malignant transformation. In addition, there have been numerous reports of multifocal dysplasia and multifocal SCC in patients with OLP, which indicate the possibility of field cancerization in OLP [1,3,6].
It is reported that some OLP lesions that turned into SCC may have been reported as OLP mistakenly, and dysplasia with lichenoid patterns should have been excluded from the study [2,7].
To address the problem of insufficient information for classifying OLP lesions that showed malignant transformation, in 2003, WHO introduced a new classification for the differentiation of OLP and OLLs, including lichenoid dysplasia lesions [5].
Oral cancers are the eighth leading cause of death from cancer, but many patients are unaware of malignant changes in their oral cavities. Early detection of oral epithelial dysplasia and malignant changes can prevent many deaths from oral cancers and provide an opportunity to limit the progression of lesions and their subsequent complications through non-invasive treatments [15].

Materials and Method
This cross-sectional retrospective study was performed The patients whose first clinical diagnosis had not been confirmed by biopsy and histological examination, the patients who did not attend the follow-up appointment, and the patients who did not agree to repeat the biopsy (if necessary) were excluded from the study. The patients who had received laser therapy, cryotherapy, or vitamin A-derived medications before the follow-up in a way that had altered the appearance of the lesions were also excluded from the study. The collected data were analyzed by the T-test, chi-square test, and logistic regression in SPSS v.21. In these analyses, p Value < 0.05 was considered statistically significant.

Results
The study identified 356 patients with a final diagnosis of OLP or OLL from April 1997 to December 2020.  Table 1). In addition, 12.1% of the patients reported being smokers or users of alcohol or drugs.
Among this group, smoking and opium use were the most common habits). Clinically, more than half of the lesions were multifocal and the most common lesion site was the buccal mucosa (Table 2). Dysplastic changes were observed in 6.2% of the patients (22 patients: 14 females (63.6%) and 8 males (36.4%)). All the malignant transformations found in the same place as previously were affected by lichen planus lesions. In patients with multiple sites affected by lesions at least one site   (Table 3). Multiple logistic regression showed that aging (p= 0.013), smoking (p= 0.0001), and abnormal thyroid (p= 0.008) increase the risk of dysplasia.

Discussion
The study investigated the malignant transformation of most commonly linked to diabetes mellitus and hepatitis C, but there is not enough evidence to prove such association, and no such association was observed in this study [23][24]. In the present study, laboratory tests showed that 12.9% of the patients had iron deficiency anemia. Considering that iron deficiency anemia is prevalent in women of reproductive age, this finding is not unexpected [25].
In a study carried out by Chen et al. [26] on the relationship between iron deficiency anemia, folic acid, B12 and OLP, 10.2% of OLP patients had iron deficiency anemia, which is close to the rate observed in this study.
In another study, Sun et al. [27] reported that 13.6% of their OLP patients had iron deficiency anemia. They ies. In addition, Iocca O et al. [32] and Giuliani et al. [33] reported same results as Idrees et al.'s study [31].
Some researchers believe that many of the lesions that suddenly show dysplastic or malignant changes in follow-ups have in fact been misdiagnosed as OLP or OLL because the original examination has missed the evidence of dysplasia [3,[5][6]. This is why WHO has published its own diagnostic criteria for differentiating OLP and OLLs from lichenoid dysplasia [2]. In the present study, dysplastic changes were present or had developed over time in the original biopsy of 6.2% of patients.
Once the archived samples used in original biopsies were re-examined based on the WHO criteria by an experienced pathologist, it was found that 50% of the cases that had been diagnosed as lichen planus had pre- In this study, the most common sites of malignant transformation were the lateral border of the tongue, the buccal mucosa, and the ventral surface of the tongue. A study by Lanfranchi et al. [35] also identified the tongue as the most common site of malignancy in OLP patients. The lateral border of the tongue and the buccal mucosa are the most commonly reported sites of the transformation of OLP to squamous cell carcinoma. However, epithelial dysplasia in OLP lesions has been reported more frequently in the buccal mucosa [6,10,[12][13][14].
In our study, dysplastic changes were observed in 22 patients (6.2%), of whom 14 were women (63.6%) and 8 were men (36.4%). The mean age of these patients at the time of dysplastic changes was 53 years. The findings of this study showed that dysplastic changes were significantly associated with aging (p= 0.013). However, in a meta-analysis conducted by Gonzalez et al. [36], they reported the same frequency for malignant transformations occurring before and after age 40. In contrast, Aghahoseyni et al. [37] reported that typically, oral cancers from OLP emerge when people are in their 60s and 70s. As in the present study, the meta-analysis of Gonzalez et al. [36] reported a higher prevalence of dysplastic changes in women, but this could be due to the higher overall prevalence of OLP in women, as the difference between these prevalence rates were not significant. Many previous studies have reported the increased risk of dysplastic and malignant transformations in OLLs [31][32][33]. However, given the clinically and pathologically similar nature of OLP and OLL in many cases, they cannot be differentiated with certainty. In our study, the pathological examination conducted based on the WHO criteria showed that 100% of the observed dysplastic changes were related to OLP lesions; this finding contradicts the reports of several previous studies [5][6]. This finding is significant because some clinicians do not consider biopsies and close follow-ups to be necessary for lichen planus lesions, whereas the risk of dysplastic changes in these lesions was significant in this study.
In this study, we found no difference between different types of OLP in potential malignant transformations.
In a study by Kaplan et al. [39], where more attention was paid to the dynamic and variable nature of OLP, it was stated that all types of OLP could undergo malignant transformations. Peng et al. [40], who studied the tumorlike microenvironments of OLP lesions, stated that the oxygen deficiency, inflammatory and immune character-istics, and acidity of these lesions could be the reasons for the higher prevalence of the development of OSCC.